It is known that platelet aggregation plays an important role in thrombus formation, in connection with a disease state. Main thrombotic diseases caused by thrombus formation include cerebral thrombosis, pulmonary thrombosis, myocardial infarction, angina pectoris, occlusion of peripheral arteries and the like, and all of these diseases require development of useful drugs. As a prophylactic or therapeutic drug, an antiplatelet agent having an inhibitory action on platelet aggregation draws public attention. Heretofore, the effect of aspirin has been widely studied, and more recently ticlopidine and cilostazol have been clinically developed. However, they are not active enough or do not act selectively enough. Therefore, a more strongly effective drug is demanded.
In addition to the above-mentioned various thrombotic diseases, various diseases are enumerated as related to platelets. Examples of these diseases include nephritis, cancer cell metastasis and the like, and recently various studies have been conducted with regard to prophylactic or therapeutic effects mainly on these diseases of an antiplatelet agent having an action of controlling the function of the platelet ("Journal of Royal College of Physicians", Vol. 7, No. 1, pp. 5-18, 1972; "Japan Clinics (Nihon Rinsho)", Vol. 4, No. 6, pp. 130-136, 1988; Anticancer Research, Vol 6, pp. 543-548, 1986).
Now, the relationship of 3(2H)-pyridazinone derivatives of the general formula (I) and their salts according to the present invention with compounds disclosed in published references will be described.
(a) German Laid Open Patent Application No. 1,670,169 (hereinafter referred to as reference (a)) discloses 3(2H)-pyridazinone derivatives having a hydrogen atom or an aliphatic, cycloaliphatic, araliphatic or aromatic group at the 2-position, a chlorine or bromine atom at the 4-position, an amino group inclusive of an aralkylamino group at the 5-position, and a chlorine or bromine atom or a hydroxy or C.sub.1 -C.sub.4 alkoxy group at the 6-position.
This reference (a) discloses a process for synthesis of the 3(2H)-pyridazinone derivatives, their application to agricultural chemicals, their application as intermediates for medicines, dyestuffs or various other chemicals, and, however, neither mentions their pharmacological activities nor gives any specific examples of such compounds. Further, such compounds are not specifically described.
(b) Japanese Unexamined Patent Publication No. 183675/1983 (hereinafter referred to as reference (b)) discloses 3(2H)-pyridazinone derivatives having a lower alkyl group at the 2-position, a hydrogen atom at the 4-position, a substituted or unsubstituted anilino group at the 5-position and a hydroxyl group or a lower alkoxy group at the 6-position. This reference (b) discloses that the 3(2H)-pyridazinone derivatives have an analgesic action, an anti-inflammatory action, an anti-allergic action and an anti-rheumatic action, but there is no specific disclosure concerning their pharmacological activities.
(c) Japanese Unexamined Patent Publication No. 301870/1988, European Laid Open Patent Publication No. 275997 and U.S. Pat. No. 4,978,665 (hereinafter referred to collectively as reference (c)) disclose 6-substituted alkoxy-5-substituted benzylamino-3(2H)-pyridazinone derivatives, which are relatively similar to the compounds of the present invention and their use as an anti-SRS-A agent.
(d) International Patent Application WO-91/16314, European Laid Open Patent Publication No. 482208 and U.S. Pat. No. 5,202,323 (hereinafter referred to collectively as reference (d)) disclose 6-substituted alkoxy-5-substituted arylamino-3(2H)-pyridazinone derivatives, which are relatively similar to the compounds of the present invention, and their use as a platelet aggregation inhibitor, a cardiotonic, a vasodilator and an anti-SRS-A agent.
The present invention relates to novel 3(2H)-pyridazinone compounds and their derivatives useful as an antiplatelet agent as an active ingredient of a prophylactic or therapeutic drug for thrombosis and other diseases attributable to pathological activation of the platelet.